A number of de novo variants in the GRB10 gene, including two de novo missense variants, have been identified in ASD probands (De Rubeis et al., 2014; Krumm et al., 2015; Turner et al., 2016; Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017; Guo et al., 2018; Tuncay et al., 2022), while a paternally-inherited and potentially deleterious missense variant in this gene was identified in an ASD proband from the ACGC cohort in Guo et al., 2018. A de novo non-coding variant that was predicted to target the GRB10 gene via chromatin interactions was identified in a Korean ASD proband from a simplex family in Kim et al., 2022; functional analysis in human induced pluripotent stem cells derived from the proband and the proband's parents demonstrated that this variant resulted in significantly reduced levels of GRB10 expression in patient-derived hiPSCs compared to parent-derived hiPSCs. The protein encoded by the GRB10 gene interacts with the proteins encoded by the ASD candidate genes GIGYF1 and GIGFY2 (Giovannone et al., 2003).
Molecular Function
The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. Overexpression of some isoforms of the encoded protein inhibits tyrosine kinase activity and results in growth suppression. This gene is imprinted in a highly isoform- and tissue-specific manner, with expression observed from the paternal allele in the brain, and from the maternal allele in the placental trophoblasts. Garfield et al., 2011 found that, within the mouse brain, Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder
